Primary liver cancers are highly malignant tumors in human and their incidences are rising in the United States. The overall survival of patients with liver cancer is grim and currently no efficient chemoprevention is available. On the basis of our published and ongoing studies, we hypothesize that the EP1 receptor plays a key role in prostaglandin-induced hepatic carcinogenesis and that inhibition of EP1 in combination with the multikinase inhibitor, sorafenib, may represent a novel and safe approach for effective chemoprevention. This hypothesis will be examined in the two specific aims using complementary animal models of hepatic carcinogenesis. Aim 1 will evaluate the combination effect of EP1 inhibition and sorafenib on the development of hepatocellular cancer induced by the hepatic carcinogen, diethylnitrosamine. Aim 2 will examine the combination effect of EP1 inhibition and sorafenib on the development of intrahepatic cholangiocellular carcinoma induced by Pten/Smad4 disruption. The proposed studies are expected to provide important implications for future chemoprevention of human liver cancer.